CS272766B2 - Method of tertiary hydroxyalkylxanthine production - Google Patents

Description

(57) A process for the preparation of compounds of formula I, wherein at least one of R ⁷ and R ⁸ is a tertiary hydroxyalkyl group of formula Ia - (CH 2 K n) -C (R ⁴ ) (OH) -CH ₃ , wherein R ⁴ is C ? -alkyl and n are from 2 to 5, and if only one of R ⁷ or R ⁸ is a group of formula Ia, the other is H or an aliphatic hydrocarbon group R 6 of up to 6 carbon atoms, the carbon chain of which is optionally interrupted to Or optionally substituted by one oxo or up to two hydroxy groups, said oxo and hydroxyl groups being separated from the ring nitrogen atom by at least two carbon atoms; and

R is C 1-6 -alkyl, comprising alkylating the 3-alkylxanthines of formula II, wherein A is H, R 1, or a group of formula Ia and B is H, R 1, benzyl or diphenylmethyl, wherein at least one of residues A and B represent a hydrogen atom, at the 1-position and / or at the 7-position in a single step or sequentially by treatment with at least one to two moles of an alkylating agent of formula III XQ, X being halogen or a sulfonic or phosphoric acid ester residue; a group of formula Ia, a group R, benzyl or diphenylmethyl, followed by a reductive cleavage of radical B, if this radical is benzyl or diphenylmethyl, or by hydrolytic elimination of an alkoxymethyl or alkoxyalkoxymethyl radical from substituent B and optionally followed by reduction of the keto group to an alcoholic function; or B represents an oxoalkyl group. The compounds produced can be used as medicaments, in particular for the treatment of peripheral and cerebral blood flow disorders.

CS 272766 Β 2%

jl

The present invention relates to a process for the preparation of novel xanthine derivatives having at least one tertiary hydroxyalkyl group at the 1 or 7-position. The compounds produced can be used as active pharmaceutical ingredients which are particularly suitable for the treatment of peripheral and cerebral blood flow disorders.

Already known are 1-oxoalkyl-3,7-dialkyl- and 7-oxoalkyl-1,3-dialkyl-anthins, respectively 1-hydroxyalkyl-3,7-dialkyl- and 7-hydroxyalkyl-1,3-dialkylxanthines with secondary alcoholic function, which are effective in promoting blood flow. Within this class of substances, the vasotherapeutic Pentoxifylline, i.e. 3,7-dimethyl 1-1- (5-oxohexyl) xanthine, has gained remarkable therapeutic importance for the medical treatment of disorders of both peripheral and cerebral blood flow. As a vasoactive drug of a new generation (cf. Schweiz, Med. Víschr. 111 (1981), pp. 637-640), it has, for example, in many countries today been firmly established among drugs used to treat peripheral arterial occlusion, while in other countries the substance is used with great success also in insufficient cerebral blood supply.

In contrast to the clinically well-established effect of this preparation, however, there is the disadvantage that both the active substance itself and its first as well as the pharmacologically active metabolite, i.e. 1- (5-hydroxyhexyl) -3,7-dimethylxanthine, · are subject to animal body and human rapid and complete biotransformation that occurs almost exclusively through the enzymatic oxidation of the 0x0- or hydroxyhexyl side chain and is associated with a pronounced first-pass effect. This means that, especially when administered orally, a significant portion of the administered dose is metabolised by drug-degrading enzymes in the first part of the liver after absorption from the stomach and intestinal tract and transport through the gastrointestinal tract to the liver, the most important organ for foreign substances. only a certain portion of the drug in the unchanged form reaches the systemic, large bloodstream. Thus, the effect of the first pass, also referred to as persystemic elimination, results in a decrease in the systemic utility of the unchanged active agent. The inherent disadvantage of the significant effect of the first passage is not that the oral dose is reduced by way of systemic circulation, but that this process generally exhibits considerable intra- and inter-individual variability (cf. Schweiz. Med. Wschr. 110 ( 1980), pp. 354-362, which make it difficult to establish a binding dose schedule and thus may adversely affect the success of the treatment.

As a result of this unsatisfactory condition, there is an understandable desire of clinicians as well as an intensive pharmaceutical research effort to find new xanthine derivatives which, with a similarly good or possibly even stronger pharmacological effect and equally excellent tolerability, have significantly higher metabolic stability and a negligible first-pass effect and which would consequently significantly improve the certainty of treatment with respect to the dosage problems described above. Preparations of this type would represent real progress in the medical treatment of peripheral and cerebral blood flow disorders, which are among the most common causes of disease and death in industrialized countries.

Surprisingly, it has now been found that the unexplored branching of the alkyl portion of the secondary hydroxyalkyl group on the hydroxyl-bearing carbon atom independently of its position on the xanthine skeleton at position 1 and / or 7 leads to compounds whose hydroxyalkyl side chain now with tertiary alcohol structure is stable to polyfunctional microsomal liver oxidases, which also satisfy the other therapeutic requirements set forth above.

The present invention relates to a process for the preparation of tertiary hydroxyalkylxanthines of the formula I

(I) wherein at least one of R 1 and R 2 is a tertiary hydroxyalkyl group of formula Ia

R * t

^(CH2) n ^{C CH} 3 ^(Ia)

OH wherein R is alkyl having up to 3 carbon atoms and n is an integer of 2 to 5, and if only one of the radicals R ¹ or R represents such a tertiary hydroxyalkyl group of the formula Ia, then the other of these radicals represents a hydrogen atom or an aliphatic hydrocarbon R 6 having from 6 to 6 carbon atoms, the carbon chain of which is optionally interrupted by up to 2 oxygen atoms or optionally substituted by one oxo group or up to two hydroxyl groups, said oxo group and hydroxyl groups being separated by at least 2 carbon atoms from the ring nitrogen atom;

R is C1-C4alkyl by alkylating 3-alkylxanthines of formula II

in which

R ² has the abovementioned meaning,

A represents a hydrogen atom, R a 'or a group of the formula Ia and

B y Namen hydrogen, R ^5, benzyl or difenyImethylovou group, wherein at least one of A and B represents hydrogen, in aprotic organic solvents, alcohols, aromatic or halogenated hydrocarbons, pyridine, optionally also in admixture with water at a reaction temperature between 0 ° C and the boiling point of the reaction mixture, preferably at a temperature between 20 and 130 ° C in the presence of basic condensing agents, such as inorganic or organic bases, or in the form of their salts, at position 1 and / or at position 7 τ step or sequentially by treatment with at least 1 or 2 moles of the corresponding alkylating agent of formula III

X - Q (ΠΙ) in which

X represents a halogen atom or a sulfonic acid ester residue or a phosphoric acid ester residue and κ

Q is a tertiary hydroxyalkyl group of the formula Ia, R, benzyl or diphenylmethyl, followed by the reductive cleavage of residue B when it is benzyl or diphenylmethyl, chemical reduction or catalytic hydrogenolysis at atmospheric pressure or pressure up to 1, 0 MPa at a temperature of from 20 to 100 ° C, or optionally hydrolytic elimination of an alkoxymethyl or alkoxyalkoxymethyl residue from the position of residue B under acidic conditions at temperatures below 100 ° C and optionally subsequent reduction of the keto group to alcohol function when A or B is oxoalkyl, by treatment with metal hydride at a temperature between 0 ° C and the boiling temperature of the reaction medium.

Suitably the process according to the invention are prepared compounds of formula I in which R ² represents a methyl or ethyl group, and only jeden'z two radicals R ¹ or R ³ represents a tertiary hydroxyalkyl group of the Yzorce la.

preferably, compounds of formula I are prepared wherein R ³ or R ³ is f (η 1) -hydroxy- (1) -methyl / pentyl, -hexyl or heptyl.

Also preferred compounds of formula I which are prepared by the process of the invention are those compounds of formula I wherein R ¹ is a tertiary hydroxyalkyl group, preferably R ¹ is / (d-1) -hydroxy- (?> -1) -methyl 1 / pentyl, hexyl Bkupinu or -heptyl, R ² is methyl or ethyl and R ³ is an alkyl group having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms or alkoxyalkyl having 1-4 carbon carbon in the alkoxy and alkyl moieties.

Preferred compounds of formula I also belong those in which R ¹ denotes 5-hydroxy-5-methylhexyl group, R ² is methyl and R ³ represents ethoxymethyl.

The groups selected for R @ ⁵ in the R @ ¹ or R @ ^{3 position} are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl, their hydroxy and oxo derivatives, the hydroxy group being optionally the oxo group in these groups is separated from the nitrogen atom by at least two carbon atoms, such as hydroxyethyl, 2- and 3-hydroxypropyl, 2,3-dihydroxyproCS 272766 B2 polyl, 2-, 3- and 4-hydroxybutyl, 2 -hydroxy-2-methylpropyl, 3,4-dihydroxybutyl, 4,5- or 3,4-dihydroxypentyl,

5,6- and 4,5-dihydroxyhexyl, 4-hydroxypentyl, 5-hydroxyhexyl, 2-oxopropyl, 3-oxobutyl, 4-oxopentyl and 5-oxohexyl, as well as alkoxyalkyl and alkoxyalkoxyalkyl groups, such as methoxymethyl, methoxyethyl and methoxypropyl, ethoxymethyl, ethoxyethyl and ethoxypropyl, propoxymethyl and propoxyethyl, methoxyethoxymethyl and methoxyethoxyethyl, as well as ethoxyethoxymethyl and ethoxy, ethoxyethyl.

A preferred embodiment of the process according to the invention consists, for example, in that a) the 3-alkoxyxanthines of the formula II in which R represents an alkyl group of up to 4 carbon atoms and A and B represent hydrogen atoms are reacted, optionally in the presence of basic agents; in the form of their salts, with alkylating agents of formula III wherein X is a halogen atom, preferably chlorine, bromine or iodine, or a sulfonic acid ester or phosphoric acid ester residue, and Q is a group of formula Ia in which an have the aforementioned of formula (Ib)

(Ib) with a tertiary hydroxyalkyl group at the R 1 position and a hydrogen atom at the R ^{1 position} , wherein R ² , R 6 and n are as defined above, and these compounds are again preferably in the presence of basic agents or in the form of their salts; with the same or another alkylating agent of the formula

III to form compounds of formula Ic

R *

C - CH ₃

AND

OH (Ic)

OH having two identical or different tertiary hydroxyalkyl groups at the substituent positions R1 ^, and R, wherein R, R * and n are as defined above, or _a ) reacting with a compound of formula III wherein X is as defined above and Q is R ^? of the above meaning, is converted to compounds of formula Id

R ⁴

in which 2 and 5

R, R, R ^ and n are as defined above.

Another preferred embodiment of (b) is that the 1,3-dialkylated xanthines of formula II, wherein R is as defined above, B is an atom. hydrogen and A denote R, suitably in the 7-position, in the presence of basic reagents or in the form of their salts, by a one-step reaction with a compound of formula III wherein Q is a group of formula Ia to form compounds of formula Id

(Id) in which 2 Δ 5

R, R, R ', and n are as defined above.

A further preferred embodiment (c) of the process according to the invention is characterized in that the 3-alkyl2-xanthines of the general formula II, in which R is as defined above and A and B are both hydrogen, also preferably in the presence of basic agents or in the form of salts, c are reacted with a compound of formula III wherein Q is R, benzyl or diphenylmethyl and X has the meaning given in formula III to form 3,7-disustituted xanthines of formula IV

R in which 2

R has the abovementioned meaning and R6 is ^R5 or a benzyl or diphenylmethyl group, and these compounds are, again preferably in the presence háziokých agents or in the form of their salts are substituted at position 1 with a compound of formula III wherein X has the above and Q is a group of formula (Ia) to give compounds of formula (Ie)

in which

About £ 4

R, R, R and n are as defined above, and those compounds of formula Ie wherein R ⁵ is benzyl or diphenylmethyl or alkoxymethyl or alkoxyalkoxymethyl are converted to compounds of formula If under reducing or hydrolytic conditions

Wherein 2 R, R * and n are as defined above, which are then optionally reacted again with the corresponding compound of formula III to give compounds of formula Ie or compounds of formula Ie.

A further embodiment, i.e. process dj, consists in reducing the compounds of the general formula Id or Ie in which R @ 1 and R @ 1 are oxoalkyl by conventional reducing agents on the keto group to the corresponding hydroxyalkylated xanthines according to the invention.

The 3-alkyl- or 1,3-dialkylxanthines of the formula XI and the alkylating agents of the formula III, which are used as starting materials, are largely known compounds or can be easily prepared according to methods known in the literature.

lacquer, the tertiary alcohols of the formula III can be obtained, for example, by the synthesis of organometallic compounds by the formation of sterically hindered haloketones of the formula Va

Hal - (CH ₂ ) _n - CO - CH ₃ (Va) in which

Hal and n are as defined above, they are reacted in the so-called extension reaction by reductive alkylation of the carbonyl group with alkyl metal compounds of the general formula

R ⁴ - M in which

M represents a metal, preferably magnesium, zinc or lithium, for example in the form of alkylmagnesium halides of the general formula R ⁴ - MgHal in which:

R ⁴ and Hal are as defined above (i.e., Grignard compounds, or in the form of alkyllithium compounds, of the general formula R ⁴ -Li in which:

R ⁴ is as defined above under conventional conditions (cf., for example, Houben-Weyl, Vol. Vl / la, Part 2 (1980), pages 928-40, in particular pages 1021 et seq. And 1104-1112).

A reaction of the same type, i.e. the reaction of the haloketones of the general formula Vb, also leads to the same objective

Hal - (CH ₂ ) _n - CO - R ⁴ (Vb) in which

Hal, R ⁴ and n are as defined above, methyl magnesium halides or methyl lithium.

Also, hydroxyketones which correspond to the general formulas Va and Vb can be directly or under temporary masking of the hydroxy group, for example by acetalization, for example by treatment with

5,6-dihydro-4H-pyran, can be converted into diols in a conventional manner by reaction with alkyl metal compounds (cf., for example, Houben-Weyl, Vol. Vl / la, Part 2 (1980), pp. 1113-1124), by selective esterification of the terminal, primary hydroxyl function, the halides or sulfonic acid or phosphoric acid anhydrides, preferably in the presence of basic agents, form compounds of formula III.

Other possibilities for the construction of tertiary alcohol derivatives of formula III are based on monometalacic-4-chloro-1-bromoalkanes on chloroalkyl metal compounds (cf. Houben-Weyl, Vol. XIII / 2 and (1973), pp. 102 and 319) and their subsequent reaction with ketones of the general formula

R ⁴ - CO - CH 3 in which

R < ⁴ > is as defined above, wherein by-product formation from the intermediate alkoxides due to their tendency to cyclize to eliminate the metal salt is prevented by appropriate temperature control or by using ω-halo-1-alkanols as starting materials in the form of tetrahydropyran-2-yl ether or also after formation of the alkoxide and the hydroxyl group (MO- (CH ₂ ) _n -Hal) using any alkyl metal compound in a conventional manner (cf., for example, Houben Weyl, et al. XIII / 2a (1973), p. 113), then in reaction with ketones of the general formula

R ⁴ - CO - CH ₃ in which

R ⁴ is as defined above to give the diols mentioned in the previous paragraph (cf. Houben-Weyl, Vol. VI / 1a and Part 2 (1980), p. 1029) and then the primary hydroxyl group is selectively esterified by treatment with suitable sulfone derivatives or phosphoric acid.

Convenient access to compounds of formula III in which R ⁴ is methyl is also afforded by the reaction of alkyl esters of 1-haloalkanoic acids (Hal- (CH 3 -COO alkyl) with two equivalents of methyl metal compounds, wherein the ester reacts via a ketone to a tertiary alcohol to introduce two methyl groups (Houben-Weyl, Vol. VI / 1a, Vol. 2 (1980), pp. 1171-1174) In the same way, ester esters of 1-hydroxycarboxylic acids can be converted, optionally protected by a hydroxy group, for example in the form of tetrahydropyran-2-yl - or methoxymethyl ether or alternatively also lactones in the form of cyclic esters, by the action of methyl metal compounds on diols (cf., for example, Houben-Weyl, Vol. VI / 1a, Part 2 (1980), pp. 1174-1179), esterification of the primary hydroxyl function with halides or sulfonic acid or phosphoric anhydrides yields active alkylating agents zorce III.

Accordingly, suitable compounds of formula III which can be prepared by the methods described above are [beta] -D-hydroxy-4-D-methylAbutyl-, -pentyl-, -hexyl- and heptyl-, [(R) -2-hydroxy] -. (C 1 -2) -methyl] -pentyl-, -hexyl-, -heptyl- and -octyl- as well as (η 3) -hydroxy- (3) -methyl) -hexyl-, -heptyl-, -octyl and -nonyl chlorides, -bromides-iodides, -sulfonates and -phosphates.

Of the compounds suitable for introducing the substituent R1 at the 1-position or the 7-position and the substituent R1 at the 7-position of the xanthine skeleton, which correspond to the general formula III, in which X is as defined above and the importance of alkoxymethyl derivatives and alkoxyalkoxymethyl derivatives to the extent that their halides are successfully used as reagents, but at least in large-scale applications can cause toxicological problems. Therefore, the use of corresponding sulfonates, which are readily available, is preferred in this particular case. for example by reacting mixed anhydrides of aliphatic carboxylic acids and aliphatic or aromatic sulfonic acids (H. H. Karger et al., J. Org. Chem. 36 (1971), pp. 528-531) with formaldehyde dialkyl acetals or formaldehyde dialkoxyalkylacetals, which reaction is clear and runs with almost 100% conv ersi (cf. H. Karger et al., J. Amer. Chem. Soc. 91 (1969), pp. 5663-5665):

R ⁷ -SO 2 -O-CO-alkyl + R ⁸ -O-CH 2 -O-R ⁸ -alkyl-CO ₂ R ⁸

-r ⁷ -so ₂ -o-ch ₂ -or ⁸ wherein alkyl = C 1 -C 4 alkyl,

R ⁷ represents an aliphatic group such as methyl, ethyl or trifluoromethyl or an aromatic group such as phenyl, 4-tolyl or 4-bromophenyl, but preferably methyl or 4-tolyl, and

Q

R represents alkyl or alkoxyalkyl groups within the meaning of the definitions of substituents A or R 6.

The reaction can be carried out both in the mass and in the anhydrous, aprotic solvent inert to the reactants at temperatures between -20 ° C and +40 ° C, preferably at temperatures between 0 ° 0 and 20 ° C. There is no need for intermediate isolation of highly reactive, hydrolysis-sensitive and heat-labile sulfonates; these intermediates are expediently used immediately as crude products for substitution on that nitrogen of xaathins, whereby the otherwise conventional addition of a basic condensing agent can be dispensed with.

The reaction of the mono- or disubstituted xanthine derivatives of formulas Ib, 1f, II and IV with the corresponding alkylating agents of formula III is generally carried out in a diluent or solvent inert to the reactants. Suitable in particular are dipolar, aprotic solvents, for example formamide, dimethylformamide, dimethylacetamide, 1-methylpyrrolidone, tetramethylurea, hexamethylphosphoric triamide, dimethylsulfoxide, acetone or butanone; however, alcohols such as methanol, ethylene glycol and its mono- or dialkyl ethers may also be used, the alkyl group having 1 to 4 carbon atoms, but both together have at most 5 carbon atoms, ethanol, propanol, isopropyl alcohol and various butyl alcohols; hydrocarbons such as benzene, toluene, or xylenes; halogenated hydrocarbons such as dichloromethane chloroform; pyridine, as well as mixtures of said solvents or mixtures with water.

The alkylation reactions are conveniently carried out in the presence of a basic condensing agent. Suitable for this purpose are, for example, alkali and alkaline earth metal hydroxides, carbonates, hydrides and alkoxides, as well as organic bases such as trialkylamines, for example triethylamine or tributylamine, quaternary ammonium hydroxides or phosphonium hydroxides and crosslinked resins with fixed, optionally substituted ammonium or phosphonium groups. Xanthine derivatives. however, they can also be used immediately in the form of their specially prepared salts, for example in the form of alkali metal salts, alkaline earth metal salts or in the form of optionally substituted ammonium or phosphonium salts, for said alkylation reaction. Further, the mono- and di-substituted xanthine derivatives can be conveniently alkylated both in the presence of the aforementioned inorganic condensation agents and in the form of their alkaline earth metal salts by the use of so-called phase transfer catalysts such as tertiary amines, quaternary ammonium or phosphonium salts. also crown ethers, preferably in a two-phase system under phase transfer catalysis conditions. Suitable, mostly commercially available phase transfer catalysts include, but are not limited to, tetraalkylammonium and tetraalkylphosphonium salts of 1 to 4 carbon atoms in the alkyl radicals, methyltrioctylammonium salts, methyltrioctylphosphonium salts, methyl 1-trialkylammonium salts of 1 to 4 carbon atoms in alkyl, myristyl-trialkylammonium salts C 1 -C 4 alkyl, phenyl C 1 -C 4 phenyltrialkylammonium and C 1 -C 4 alkylbenzyltrialkylammonium salts, Cetyltrimethylammonium salts as well as C 1 -C 12 alkyltriphenylphosphonium salts and benzyltriphenylphosphonium salts, wherein: As a rule, compounds having a larger and symmetrical cation have proven to be more effective.

6,

The introduction of the groups of the formula Ia as well as the groups R and R according to the above-mentioned processes is generally carried out at a reaction temperature between 0 ° C and the boiling point of the reaction medium in use, preferably at temperatures between 20 ° C and 130 ° C. The reaction time may be less than one hour or up to several hours.

The reaction of the 3-alkylxanthines of the formula II to the compounds of the formula Ic requires the introduction of two tertiary hydroxyalkyl groups. In this case, either the same or different substituents or alternatively two hydroxyalkyl groups of the same type can be coupled to the xanthine residue without isolation of the intermediates in a single reaction step.

Reductive cleavage of the benzyl or diphenylmethyl group from the compounds of the formula Ie to give xanthine derivatives of the formula 1f containing a hydrogen atom at the 7-position is carried out under standard conditions which have been elaborated primarily in the protecting group technique for the synthesis of alkaloids and peptides; so they can be assumed to be widely known. In addition to chemical reduction, in particular in the case of benzyl derivatives with sodium in liquid ammonia (cf. Houben-Weyl, Vol. XI / 1 (1957), pp. 974-1975), the elimination of both of the above aralkyl groups by catalytic hydrogenolysis in the presence of catalysts noble metals (cf. Houben-Weyl, Vol. XI / 1 (1957), pp. 968-971 and Vol. IV / 1c, Part 1 (1980), pp. 400-404). The reaction medium is usually a lower alcohol (optionally with the addition of formic acid or also ammonia), an aprotic solvent such as dimethylformamide or, in particular, glacial acetic acid; However, mixtures with water may also be used. Particularly suitable hydrogenation catalysts are palladium black and palladium on charcoal or barium sulphate, while other noble metals such as platinum, rhodium and rutheniura are often prone to side reactions due to competitive core hydrogenation and are therefore only applicable under certain conditions. The hydrogenolysis is conveniently carried out at temperatures between 20 ° C and 100 ° C and at atmospheric pressure or preferably at a slightly elevated pressure of up to about 1.0 MPa, reaction times of from several minutes to several hours being generally required.

The 1,3,7-trisubstituted xanthines of formula (Ie) which contain an alkoxymethyl group or an alkoxyalkyloxymethyl group in the R 1 position represent Ο, Ν-acetals. Accordingly, their substituents at the 7-position can be cleaved under normal conditions by acid hydrolysis (cf. Houben-Weyl, Vol. VI / 1b (1984), pp. 741-745), and the 7H-derivatives of formula 1f are also formed. . Preferred hydrolytically eliminable groups are, for example, methoxy, ethoxy, and propoxymethyl, as well as methoxyethoxymethyl and ethoxyethoxymethyl. The reaction is preferably carried out with heating in dilute mineral acids such as hydrochloric acid, sulfuric acid, optionally with the addition of glacial acetic acid, dioxane, tetrahydrofuran or its lower alcohol as co-solvents. Also suitable are perchloric acid organic acids, such as trifluoroacetic acid, formic acid and acetic acid, together with a catalytic amount of mineral acids. In particular, alkoxyalkoxymethyl derivatives can also be cleaved with anhydrous Lewis acids such as zinc bromide and titanium tetrachloride. medium, preferably in dichloromethane or chloroform, wherein the intermediate 7-bromomethyl or 7-bromosine derivatives are self-hydrolyzed in connection with aqueous work-up. When cleaving in a solution containing a mineral acid, the reaction temperature must be chosen so as to avoid appreciable dehydration of the tertiary hydroxyalkyl group at the 1-position. The reaction temperature should therefore generally be below 100 ° C.

The reduction of the xanthines of the formulas Id and Ie which contain an oxoalkyl group in the position of the substituents R @ 1 and R @ ⁶ respectively to the corresponding hydroxyalkyl derivatives can in principle be carried out by means of non-noble metals as well as by catalytic hydrogenation. under very mild conditions and with high yields, with simple metal hydrides (MH), complex metal hydrides

Ί p / ^FCI (M Η) ^ / or organometallic hydrides (cf. Houben-Weyl, Vol. IV / 1 d (1981), p.

267-282 and Vol. VI / 1b (1984), pp. 141-155). Among the many complex metal hydrides that are useful for reducing ketones are, for example, the most commonly used reagents, i.e., lithium alanate, lithium borate and especially sodium borate, which, due to its low reactivity, is readily available and especially allows work in alcoholic, alcoholic-aqueous and Pure aqueous solutions or suspensions. Nitriles such as acetonitrile may also be used as reaction medium in addition to the otherwise customary inert solvents such as ethers such as diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons and pyridine. The hydrogenation, which is conveniently carried out at temperatures between 0 ° C and the boiling point of the solvent, preferably at room temperature, generally proceeds rapidly and is completed within a few minutes to a few hours.

3

In compounds where one of R and R ^J represents a dihydroxyalkyl group, a dihydroxyalkyl group can be built, optionally introduced by conventional methods as described for example in EP-75850.

The tertiary hydroxyalkylxanthines of formula I may contain one or two asymmetric carbon atoms depending on the chain length of the alkyl R (at least 2 carbon atoms) and / or the substituent structure R (e.g. 2-hydroxypropyl) and are therefore present in stereoisomeric forms. The invention therefore relates to both pure stereoisomeric compounds and mixtures thereof.

The xanthine derivatives of the formula (I) produced by the process of the invention are suitable on account of their valuable pharmacological properties and favorable metabolic properties. properties, for example against multifunctional microsomal liver oxidases, in an excellent manner for use as an active ingredient of medicaments, in particular those which allow more effective prophylactic and curative treatment of diseases caused by peripheral and cerebral blood flow disorders such as peripheral arterial occlusion and thus represent drug enrichment. These compounds may be administered alone, for example in the form of microcapsules, in admixture with each other or in combination with suitable carriers.

Drugs containing the compounds produced according to the invention are generally administered orally or parenterally, although in principle rectal administration is also possible.

Suitable solid liquid galenic preparations are, for example, granules, powders, tablets, dragees, (micro) capsules, suppositories, syrups, emulsions, suspensions, aerosols, drops or injectable solutions in the form of ampoules, as well as sustained-release formulations. they are generally used in the manufacture of adjuvants such as carriers, disintegrants, binders, coatings, hot suspenders, lubricants and lubricants, flavorants, sweeteners or co-solvents. Frequently used excipients are, for example, magnesium carbonate, titanium dioxide, milk sugar, mannitol and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents such as sterile water, alcohols, glycerin and polyhydric alcohols.

Preferably, the pharmaceutical compositions are prepared and administered in unit dosage form, each unit containing as an active ingredient a particular dose of a compound of formula I. For solid dosage units such as tablets, capsules and suppositories, the dosage may be up to 1000 mg, preferably 100 to 600 mg, and for injection solutions in the form of ampoules, this dose is up to 300 mg, but is preferably 20 to 200 mg.

For the treatment of adult patients, depending on the efficacy of the compounds of formula I, daily doses of from 100 to 2000 mg of active compound, preferably 300 to 900 mg, for oral administration and 10 to 500 mg, preferably 20 to 200 mg, intravenous application. However, higher or lower doses per day may also be administered as appropriate. The daily dose may be administered as a single administration in the form of a single dose.

or in the form of several smaller dosage units, as well as multiple administration of divided doses at certain intervals.

Finally, the xanthine derivatives of the formula I can also be combined with other suitable active ingredients, such as antithrombotics, antihyperlipidemics, analgesics, sedatives, antidepressants, antianginal agents, cardiotonics, antiarrhythmics, diuretics, antihypertensives, including blockers receptors and calcium channel blockers, plasma replacement, as well as other vasotherapeutics.

The structure of all the compounds mentioned hereinbelow were confirmed by elemental analysis and IR spectra values ^L and H-NMR spectra. The compounds of formula 1 which were prepared according to the examples below, as well as the compounds produced in an analogous manner, are summarized in Table 1.

In the following examples, ether is understood to mean diethyl ether and vacuum or lower pressure is to be understood by vacuum or lower pressure, which is achieved using a water pump.

Example 1

7- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 1)

a) 1-chloro-5-hydroxy-5-methylhexane

CH ci - (ch ₂ ) ₄ - C - ch ₃

OH

a.j.) from 1-chloro-5-bexanone:

To 44.9 g (0.6 mol) of methyl magnesium chloride as a 20% solution in tetrahydrofuran and 200 ml of absolute ether was added dropwise with stirring at 0-5 ° C.

67.3 g (0.5 mol) of 1-chloro-5-hexanone in 50 ml of anhydrous ether. The reaction mixture was stirred for 1 hour at room temperature and then for an additional hour at reflux. The resulting tertiary alkoxide was quenched by the addition of 50% aqueous ammonium chloride solution, the ether phase was separated and the aqueous phase was extracted with ether. The combined ether phases are washed successively with aqueous sodium bisulfite solution and aqueous sodium bicarbonate solution, as well as water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was traction distilled under reduced pressure.

Yield: 64.1 ε (S5, 1% of theory).

Boiling point 95-97 ° C / 2000 Pa.

Refractive index n ^ = 1.4889 Sum formula: DyH- ^ ClO (molecular weight = 150.65) -.

This compound can also be prepared in an analogous way from 5-chloropentanoic acid methyl ester or ethyl ester by reaction with twice the molar amount of methyl magnesium chloride (cf. Example 10a). .... . "_.

and ₂ ) from 1-bromo-4-chlorobutane and acetone:

To 24.3 ε (1 gram) of magnesium was added 10 g of 1-bromo-4-chlorobutane after coating with anhydrous ether. Once the reaction has started, a further 161.5 ε of dihaloalkane (total 1 mol) dissolved in 200 ml of absolute ether is added dropwise to the reaction mixture so that the reaction mixture boils slightly.

After completion of the metal reaction, 52.3 ε (0.9 mol) of acetone is added dropwise and the reaction mixture is mixed with an equal volume of ether. After stirring for another 2 hours at room temperature, 100 ε of ice and saturated ammonium chloride solution are added, the ether layer is separated and the aqueous phase is extracted several times with ether. The combined organic phases are washed with a small amount of water, dried over sodium sulphate, the ether is distilled off in vacuo and the distillation residue is fractionally distilled under reduced pressure.

Yield: 71.6 g (52.8% of theory).

Boiling point 95 ° C / 1700 Pa.

b) 7- (5-hydroxy-5-methylhexyl) -3-methylxanthine g (0.5 mol) of 3-methylxanthine ee was dissolved in 500 ml of 1N sodium hydroxide solution (0.5 mol) in the hot state. The solution is then filtered, the water is distilled off from the filtrate under reduced pressure, and the residual sodium salt is dried under high vacuum. After addition of 1.5 liters of dimethylformamide and 75.3 g (0.5 mol) of 1-chloro-5-hydroxy-5-methylhexane, the reaction mixture is heated at 110 ° C for 6 hours, then the reaction mixture is filtered while hot. The mixture was evaporated under reduced pressure and the residue was dissolved in 1 liter of hot 1N sodium hydroxide solution. The hot solution is filtered and after cooling to room temperature, a 6N hydrochloric acid solution is added dropwise with stirring to pH 9. The precipitate is filtered off, washed neutral and dried in vacuo.

Yield: 100.5 g (71.7% of theory).

Mp 228-230 ° C.

Summary formula: 0 - ^^ ¾Ο ^ 4θ3 (molecular weight 280.3) ·

Analysis:

H, 7.19; N, 19.99.

Found: C, 55.60; H, 7.31; N, 19.92.

Example 2 1,7-Bis- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 2)

A mixture of 14 g (0.05 mol) of 7- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Example 1b),

8.2 g (0.054 mol) of 1-chloro-5-hydroxy-5-methylhexane (Example 1a) and 7.5 g (0.054 mol) of potassium carbonate in 300 ml of dimethylformamide are stirred for 18 hours at 110 ° C, then the reaction mixture is filtered while hot and the filtrate is concentrated under reduced pressure. The residue is taken up in chloroform, washed first with dilute sodium hydroxide solution and then with water until neutral, dried over sodium sulfate and the solvent is distilled off under reduced pressure.

Preferably, the crude product can be converted to an analytically pure material by filtration through a silica gel column using a 10: 1 mixture of chloroform and methanol followed by stirring in diisopropyl ether.

Yield: 14.9 g (75.5% of theory).

Melting point: 93-95 ° C.

Analysis for:

^ 20 ^ 34 ^Ν 4θ4 (MW 394.5).

Analysis:

C, 60.89; H, 8.69; N, 14.20.

Found: C, 60.89; H, 8.98; N, 14.17.

This compound can be obtained, inter alia, by a one-step dialkylation of 3-methylxanthine using twice the molar amount of 1-chloro-5-hydroxy-5-methylhexane.

Example 3

7- (5-hydroxy-5-methylhexyl) -3-methyl-1-propylxanthine (Compound No. 3)

g (0.14 mol) of 7- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Example 1b) is heated together with 18.5 g (0.15 mol) of 1-bromopropane and 20.7 g ( 0.15 mol) of potassium carbonate in 300 ml of dimethylformamide is stirred at 130 DEG C. for 8 hours. After cooling and concentration under reduced pressure, dilute sodium hydroxide solution was added and then the mixture was carefully extracted with chloroform. The organic phase, after washing with water until neutral, drying over sodium sulfate and evaporation under reduced pressure, affords an oily crude product which is most easily purified by filtration through a silica gel column using chloroform / methanol (25: 1) as the eluent and stirring in diisopropyl ether.

Yield: 36.5 g (80.9% of theory).

Melting point: 59-60 ° C.

Summary formula:

^ 16 ^ 26 ^ 4 ^ 3 and ^{MO Elat} l l ^ag weight 322.4).

Analysis:

C, 59.61; H, 8.13; 17.38%. Found: C, 59.43; H, 8.01; N, 17.29.

Also alkylation of 3-ethyl-1-propylxanthine with 1-chloro-5-hydroxy-5-methylhexane, carried out analogously to Example 4 below, leads to the same compound.

Example 4

7- (5-hydroxy-5-methylhexyl) -1,3-dimethylxanthine (Compound No. 4)

CH ₃ h ₃ cn

(CH 3), - C - CH ₃ i

OH

0 '• N

CH,

21.8 g (0.1 mol) of 1,3-dimethylxanthine in the form of the potassium salt (prepared analogously to Example 1b) from 1,3-dimethylxanthine and an equimolar amount of potassium hydroxide in water) are stirred with 16.6 g (0, 11 mol) of 1-chloro-5-hydroxy-5-methylhexane. of Example 1a) in 500 ml of dimethylformamide for 18 hours at 120 ° C. The reaction mixture was allowed to cool, concentrated in vacuo, 4N sodium hydroxide solution was added to the residue, and the product was extracted with chloroform. The extract washed with water until neutral is evaporated after drying under reduced pressure. The evaporation residue is recrystallized from isopropanol / ether.

Yield: 20.7 g (70.3% of theory).

Melting point: 106 to 107 ° C.

Analysis for:

H, 7.53; N, 19.03. ^C 14 H 22 N 4 ^O 3 (MW 294.36) requires C, 57.13; H, 7.53;

Found: 57.39% H, 7.67% H, 19.28% N.

Alternatively, this compound can be obtained, inter alia, from 7- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Example 1b) and iodomethane in analogy to Example 3.

Example 5

7-Ethoxymethyl-1- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 5)

(a) 7-ethoxymethyl-3-methylxanthine -

and ^) with ethoxymethyl chloride:

g (0.5 mol) of 3-methylxanthine is dissolved in a hot solution of 20 g (0.5 mol) of sodium hydroxide in 400 ml of water. After filtration, the reaction mixture is concentrated in vacuo, distilled several times with methanol and the sodium salt is dried under high vacuum.

The dried salt was suspended in 1.3 L of dimethylformamide, 47.3 g (0.5 mol) of ethoxymethyl chloride was added with stirring, and the mixture was stirred at 110 ° C for 18 hours. The reaction mixture is filtered under hot conditions, evaporated under reduced pressure, dissolved in 500 ml of 2N sodium hydroxide solution and extracted with chloroform to remove 1,7 dialkylated 3-methylxanthine as a by-product. The alkaline aqueous solution is treated by adding 2N hydrochloric acid solution with stirring at pH 9, the resulting crystalline product is filtered off, washed first with water to remove chloride ions and then with methanol, and then dried under reduced pressure.

Yield: 77.6 g (69.2% of theory).

Melting point: 263-264 ° C.

Empirical formula ^C ^ g x2®4®3 (molecular weight 224.2).

and ₂ ) with ethoxymethyl 4-toluenesulfonate:

(starting from 4-toluenesulfonic acid chloride and sodium acetate)

104.9 g (0.55 mol) of 4-toluenesulfochloride are dissolved in 100 ml of dimethylformamide and 45.1 g (0.55 mol) of anhydrous sodium acetate are added under stirring and with ice-cooling. After stirring for an additional 1 hour at room temperature, 78.1 g (0.75 mol) of formaldehyde diethyl acetal was added dropwise to the reaction mixture. The reaction mixture was stirred again at room temperature for 1 hour, and then 83 g (0.5 mol) of 3-methylxanthine was added. Thereafter, the reaction mixture is heated at 90 DEG C. for 2 hours without the addition of a basic condensing agent, the precipitated product is filtered off cold, additionally washed with cold dimethylformamide and water to remove chloride ions, rinsed with methanol and recrystallized from dimethylformamide.

Yield: 98.1 g (87.5% of theory).

Mp = 265 ° C.

and ^) with ethoxymethyl 4-toluenesulfonate (using 4-toluenesulfonic acid and acetic anhydride as starting materials)

With stirring and cooling, 226 g (1,2-molar 4-toluenesulfonic acid monohydrate) is dissolved in 450 g (4.4 mol) of acetic anhydride, and then the resulting solution is heated at 70 DEG C. for 30 minutes. distilled off under reduced pressure, the residue was diluted with 100 ml of toluene and the solution was stirred under cooling into 450 ml of dimethylformamide so that the internal temperature did not exceed 20 DEG C. After dropwise addition of 230 g (2.2 mol) of formaldehyde diethyl acetal and stirring at 20 ° C: 166.1 g (1 mol) of 3-methylxanthine are added The reaction mixture is heated and stirred at 100 ° C for 1 hour, then cooled, the precipitated product is filtered off, washed successively 250 ml of dimethylformamide, water and methanol each and recrystallized from dimethylformamide.

Yield: 201 g (89.7% of theory).

Mp: 264-265 ° C.

b) 7-ethoxymethyl-1- (5-hydroxy-5-methylhexyl) -3-methylxanthine

H.

CH ₂ - 0 - Cff ₂ - CR i

CH.

CHCS 272766 B2 ί To 11.2 g (0.05 mol) of 7-ethoxymethyl-3-methylxanthine in 300 ml of dimethylformamide was added 7.5 g (0.054 mol) of potassium carbonate and 8.2 g (0.054 mol) of 1-chloro -5-hydro ·; xy-5-methylhexane (Example 1a), whereupon the reaction mixture is heated to 110 ° C with stirring for 5 hours. The reaction mixture is filtered while hot, concentrated in vacuo, the residue is taken up in chloroform, washed first with 1N sodium hydroxide solution and then with water until neutral, dried over sodium sulphate, the solvent is distilled off under reduced pressure and the residue is recrystallized from diisopropyl ether. with the addition of ethyl acetate and petroleum ether.

Yield: 14.1 g (83.3% of theory).

102-103 ° C.

For C ^ 16 ^ ^ 16 ^ 26¾¾¾¾¾ (MW 338.4) calculated C 56.79, H 7.74, N 16.56%; Found: C, 56.76; H, 7.82; N, 16.59.

Example 6 1- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 6)

(a) catalytic hydrogenolysis of 7-benzyl-1- (5-hydroxy-5-methylhexyl) -3-methylxanthine: 7-b enzyme 1-3-methylxanthine

To a suspension of 83% (0.5 mol) of 3-methylxanthine in 500 ml of methanol is added 20 g (0.5 mol) of sodium hydroxide dissolved in 200 ml of water and the mixture is stirred at 70 ° C for 1 hour and then at the same temperature. 85.5 g (0.5 mol) of benzyl bromide are added dropwise and the reaction mixture is maintained at a temperature between 70 and 80 ° C for 5 hours. The reaction mixture was then cooled, filtered cold, washed with water on the filter, dissolved in 1000 ml of 1N sodium hydroxide solution (hot), filtered and slowly adjusted to pH 9.5 with stirring by adding 4N hydrochloric acid. The crystallizate is filtered off from the still hot solution, washed with water until the chloride ions are removed and dried in vacuo.

Yield: 81.7 g (63.8% of theory).

Melting point: 262-264 ° C.

Summary formula:

° 13 ^ 12 ^ 4θ2 (molecular weight 256.2).

7-Benzyl-1- (5-hydroxy-5-methylhexyl) -3-methylxanthine

A mixture of 20.5 g (0.08 mol) of 7-benzyl-3-methylxanthine, 12.4 g (0.09 mol) of potassium carbonate and 13.6 g (0.09 mol of tertiary alcohol from Example 1a) in 300 ml dimethylformamide was heated at 110-120 ° C for 8 hours, filtered hot and evaporated under reduced pressure. The residue is taken up in chloroform, washed first with 1N sodium hydroxide solution, then with water until neutral, dried, the solvent is distilled off under reduced pressure and the solid residue is recrystallized from ethyl acetate with the addition of petroleum ether.

Yield: 23.8 g (80.3% of theory).

Melting point: 109-111 ° C.

Analysis for:

δ20.46-4.43 (molecular weight 370.5) calculated 64.84% C, 7.07% H, 15.12% N; .

Found: C 65.00, H 7.21, H 15.24.

1- (5-hydroxy-5-methylhexyl) -3-methylxanthine

14.8 g (0.04 mol) of the above-mentioned 7-benzylxanthine are hydrogenated in 200 ml of glacial acetic acid in the presence of 1.5 g (5%) of palladium on activated carbon at 60 DEG C. and at a pressure of 0.35 MPa. shaking for 24 hours. After cooling, the mixture was covered with nitrogen, the catalyst was filtered off, the filtrate was concentrated under reduced pressure and the solid residue was recrystallized from ethyl acetate.

Yield: 9.6 g (85.6% of theory).

Melting point: 192-193 ° C.

Analysis for ^C 13 ^H 20 ^N 4 ° 3 (MW 280.3).

H, 7.19; N, 19.99. Found: C, 55.63; H, 7.30; N, 20.00.

(h) hydrolytic dealkoxymethylation from 7-ethoxymethyl-1- (5-hydroxy-5-methylhexyl) -3-methylxanthine (from Example 5b):

13.5 s (0.04 mol) of the xanthine derivative of Example 5b in a mixture of 300 ml of 1N hydrochloric acid solution and 30 ml of glacial acetic acid are heated at 70 ° C for 2.5 hours with stirring, after cooling the reaction mixture is neutralized with 4N sodium hydroxide solution and then the product was extracted with chloroform. The chloroform solution was dried, evaporated to dryness under reduced pressure, and the evaporation residue was filtered through a silica gel column using a 10: 1 mixture of chloroform and methanol as the eluent and recrystallized from ethyl acetate.

Yield: 7.7 g (68.7% of theory).

Melting point: 191-192 ° C.

Hydrolytic cleavage of the propoxymethyl group from 1- (5-hydroxy-5-methylhexyl) -3-methyl-7-propoxymethylxanthine (cf. Compound No. 34 of the same type) gives the 7H-derivative in 75% yield. ..... ...

Example 7 1- (5-hydroxy-5-methylhexyl) -3-methyl-7 '(2-oxopropyl) xanthine (Compound No. 7)

a) 3-methyl-7- (2-oxopropyl) xanthine

CH

166 g (1 mol) of 3-methylxanthine and 110 g (1.3 mol) of sodium bicarbonate are suspended in 500 ml of dimethylformamide, the suspension is heated to 100 DEG C. with stirring and then 111 g (1, 2 mol) of chloroacetone. The reaction mixture is then stirred for 2 hours at 100 [deg.] C., cooled and the precipitate formed is filtered off and washed five times with 50 ml of dimethylformamide each time. After removal of the product with 1N sodium hydroxide solution at 60 ° C, dilute hydrochloric acid is added until pH 9, then the mixture is filtered, the residue on the filter is washed until the chloride ions are removed, rinsed with methanol and dried in an oven at 80 ° 0.

Yield: 190 g (85.5% of theory).

_'QTeplota,: mp 300 ° C.

Summary formula: ^C 9 I ^{x x li} 4 ° 3 ·? (MW 222.2).

When sodium carbonate or potassium carbonate is used as the basic condensation agent, when the sodium or potassium salts of 3-methylxalin are used as starting materials, the yields obtained are substantially lower (not more than 70%). .

b) 1- (5-hydroxy-5-methylhexyl) -3-methyl-7- (2-oxopropyl) xanthine

22.2 g (0.1 mol) of xanthine from step a) are reacted with 16.6 g (0.11 mol) of 1-chloro-5-hydroxy-5-methylhexane (Example 1a) and 15.2 g. (0.11 mol) of potassium carbonate in 500 ml of dimethylformamide under the conditions described in Example 2 and then worked up. The reaction product purified by column chromatography is then recrystallized from diisopropyl ether with the addition of ethyl acetate at boiling point.

Yield: 26.7 g (79.4% of theory).

Melting point: 78 to 80 ° C.

For C C ^ gEL NN ^O ^ (MW 336.4) calculated.57.13% C, 7.19% 2, 16.6% N;

Found: C, 56.85; H, 7.28; N, 16.41.

Example 8 1- (5-hydroxy-5-methylhexyl) -7- (2-hydroxypropyl) -3-methylxanthine (Compound No. 8)

OH

To a suspension of 16.8 g (0.05 mol) of 1- (5-hydroxy-5-methylhexyl) -3-methyl-7- (2-oxopropyl) xanthine (Example 7b) in 200 ml of methanol was stirred at room temperature with stirring. adds

0.95 S (0.025 mol) of sodium borate. After stirring for several hours, a clear solution was formed.

The excess hydride is quenched by the addition of 1 ml of glacial acetic acid, the mixture is evaporated under reduced pressure, the residue is taken up in chloroform, the chloroform solution is washed successively with dilute sodium hydroxide and water, dried over sodium sulfate and concentrated to dryness under reduced pressure.

The solid crude product was recrystallized from ethyl acetate.

Yield: 15.3% (90.4% of theory).

Melting point: 119-120 ° C.

Analysis: Calculated: C, 56.79; H, 7.74; N, 16.56.

Found: C, 56.52; H, 7.86; N, 16.47.

The title compound can also be prepared from 3-methylxanthine as a starting material in a two-step reaction by first introducing with 1-chloro-2-propanol

The 2-hydroxypropyl group to the 7-position (melting point: 278-280 ° C, 69.6% yield) and then alkylated at the 1-position with 1-chloro-5-hydroxy-5-methylhexane (Example 1a) (yield 67.5) % of theory).

Example 9 1- (4-hydroxy-4-methylpentyl) -3-methyl-7-propylxanthine (Compound No. 12)

a) 1-chloro-4-hydroxy-4-methylpentane

44.9 g (0.6 mol) of methylmagnesium chloride as a 20% solution in tetrahydrofuran was treated in anhydrous ether with 60.3 g (0.5 mol) of 1-chloro-4-pentanone according to the procedure of Example 1aj) and then is processed.

Yield: 42.7 g (62.5% of theory).

Boiling point: 77-78 ° C / 1700 Pa.

Summary formula: C 8 H 10 ClO (molecular weight 136.6).

b) 1- (4-hydroxy-4-methylpentyl) -3-methyl-7-propylxanthine

To a suspension of 20.8 g (0.1 mol) of 3-methyl-7-propylxanthine in 250 ml of methanol was added a solution of 5.6 g (0.1 mol) of potassium hydroxide in 100 ml of methanol. Heating gave a clear solution, which was evaporated to dryness under reduced pressure. The residual potassium salt of the xanthine derivative was mixed with 500 ml of dimethylformamide and 15.0 g (0.11 mol) of the tertiary alcohol from step a) after sharp drying under high vacuum, and the reaction mixture was stirred at 80 ° C for 18 hours. Work-up of the reaction mixture was carried out in an analogous manner to Example 5 b), whereby 25.1 g of crude product (81.4% of theory) were obtained. The crude product can be purified by recrystallization from diisopropyl ether with the addition of a small amount of ethyl acetate at boiling point.

Yield: 19.2 g (62.3% of theory).

Melting point: 96-9 ° C Analysis for:

C15 H20 N3 O3 (MW 308.4) calculated C 58.42, H 7.84%, 18.17 96%; found: 58.49 96 C, 7.82 96 H, 18.19 96 H.

In addition, the title compound can be prepared by alkylating (1- (4-hydroxy-4-methylpentyl) -3-methylxanthine with 1-bromo- or 1-chloropropane at the 7-position analogously to Example 3).

Example 10

3-ethyl-1- (6-hydroxy-6-methylheptyl) -7-methylxanthine (Compound No. 13)

(a) 1-bromo-6-hydroxy-6-methylheptane;

89.8 g (1.2 mol) of methylmagnesium chloride as a 20% solution in tetrahydrofuran are introduced together with 500 ml of anhydrous ether and a solution of 102.3 g (0.46 mol) of ethyl ester is added dropwise with stirring at 0-5 ° C. Of 6-bromohexanoic acid in 100 mL of absolute ether. Thereafter, the reaction mixture was further stirred at room temperature for 30 minutes and refluxed for 2 hours. The reaction mixture is poured onto ice and 50% aqueous ammonium chloride solution is added until the precipitate is completely dissolved. The mixture is then extracted several times with ether, the ethereal extract is washed successively with aqueous sodium bisulfite solution and aqueous sodium hydrogencarbonate solution as well as with water, dried over sodium sulfate, filtered and the solvent is removed under reduced pressure. The residue was subjected to fractional distillation.

Yield: 80.2 g (83.4% of theory).

Boiling point: 77-79 ° C / 200 Pa.

Summary formula:

C 8 H 11 OBr (MW 209.1).

b) 3-ethyl-1- (6-hydroxy-6-methylheptyl) -7-methylxanthine

23.2 g (0.1 mol) of the potassium salt of 3-ethyl-7-methylxanthine (prepared analogously to Example 9b) were added after the addition of 500 ml of dimethylformamide and 23.0 g (0.11 mol) of the tert. of the bromo alcohol from step a) is heated to 120 ° C for 8 hours with stirring. Thereafter, the reaction mixture is worked up as described in Example 5b), whereby an oily product is formed which crystallizes over a longer period of time and then recrystallizes from diisopropyl ether.

Yield: 23.7 g (73.5% of theory).

Melting point: 86-87 ° C.

Analysis for:

δ 6 ^ 26 ^ 4θ3 (θ ° C ^e spherical mass 322.4) calculated 59.61% C, 8.13% H, 17.38% N;

Found:% C, 59.68;% H, 8.16;% N, 17.54.

The same compound was also obtained by methylating the 3-ethyl-1- (6-hydroxy-6-methylheptyl) xanthine with methyl bromide, methyl iodide, methylsulfonate or dimethylsulfate according to Example 3.

Example 11

7- (3,4-dihydroxybutyl) -1- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 55)

a) 7- (3-Butenyl) -3-methylxanthine

g (0.25 mol) of 3-methylxanthine monosodium salt (prepared as described in Example 1b) and 34.8 g (0.25 mol) of 97% 1-bromo-3-butene are stirred in 750 ml of dimethylformamide for 8 hours. hours at 110 ° C. The precipitated sodium bromide is then removed by filtration with an even hot reaction mixture, the filtrate is evaporated under reduced pressure, the solid residue is dissolved in 250 ml of 2N sodium hydroxide solution, the solution is heated to about 65 ° C and 2N hydrochloric acid solution is added. Acids up to pH 9 After cooling, the solid formed is filtered off, washed with water until the salts are removed and, after washing with methanol, dried under vacuum.

Yield: 32 g (58.1% of theory).

Melting point: 242-245 ° C.

Summary formula:

θ10 ^ 12 ^ 4 ° 2 (molecular weight 220.2).

b) 7- (3-Butenyl) -1- (5-hydroxy-5-methylhexyl) -3-methylxanthine

g (0.1 mol) of xanthine from step (a) is reacted with 16.6 g (0.11 mol) of 1-chloro-5-hydroxy-5-methylhexane (cf. Example 1a) and 15.2 g ( 0.11 mol) of potassium carbonate in 500 ml of dimethylformamide under the conditions described in Example 2 and the reaction mixture was worked up. The reaction product is obtained without previous purification by column chromatography by a single recrystallization from ethyl acetate with the addition of petroleum ether at boiling point pure.

Yield: 25.7 g (76, S% of theory).

Melting point: 105-107 ° C.

Summary formula:

θ17®26 ^ 4θ3 ( ^m ° 4external mass 334.4).

o) 7- (3,4-epoxybutyl) -1- (5-hydroxy-5-methylhexyl) -3-methylxanthine

CH - CH? \ / ² O

To a solution of 22 g (0.066 mol) of xanthine from step b) in 250 ml of chloroform is added over about 15 minutes under nitrogen and with stirring at room temperature.

15.8 g (0.078 mol) of 85% 3-chloroperbenzoic acid. After stirring at room temperature for 48 hours, a 10% sodium dithionite solution is added sequentially to wash,

10%; bicarbonate solution and water, then dried in vacuo and evaporated to give an almost quantitative yield of an epoxide (Cid YÍgg produktuNN ^O;; molecular weight 350.4) as an oily product, which can be used immediately in the following. reaction step d).

d) 7- (3,4-dihydroxybutyl) -1- (5-hydroxy-5-methylhexyl) -3-methylxanthine

ch ₃

A solution of 23 g (0.065 mol) of the compound from step (o) in a mixture of 120 ml of tetrahydrofuran and 80 ml of water was mixed with 0.4 ml (70%) of perchloric acid under stirring at room temperature. After stirring at room temperature for 5 days, the mixture was neutralized with saturated sodium bicarbonate solution, the reaction mixture was evaporated in vacuo, the residue taken up in chloroform and the chloroform solution purified by column chromatography on silica gel using a 10: 1 mixture of chloroform and methanol. as eluent.

Yield: 19.4 g (81% of theory).

Melting point: 116-118 ° C.

Analysis for:

C ^ HHggNN ^O ^ (MW 368.4) calculated C 55.42%, H 7.66%, N 15.21%;

Found: C 55.13, H 7.84, N 14.98.

Example 12

7- (2,3-dihydroxypropyl) -1- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 56)

a) 7- (2,3-dihydroxypropyl-3-methylxanthine)

- CHň

AND

The OH g (0.5 mol) of 3-methylxanthine is dissolved in 1250 ml of dimethylformamide, and 12 g (0.5 mol) of sodium hydride are added in portions while stirring at room temperature. The reaction mixture is stirred for an additional 30 minutes, after which 55.3 g (0.5 mol) of 1-chloro-2,3-propanediol in 100 ml of dimethylformamide are added dropwise and the reaction mixture is heated at 100 DEG C. with stirring for 18 hours. The work-up is carried out as described in Example 11a. ,

Yield: 66.6 g (55.5% of theory).

Mp 302 DEG-304 DEG.

Summary formula:

C 8 H 8 N 2 O 2 (molecular weight 240.2).

b) 7- (2,3-dihydroxypropyl) -1- (5-hydroxy-5-methylhexyl) -3-methylxanthine

ch ₃

A mixture of 18 g (0.075 mol) of the xanthine derivative from step a), 12.5 g (0.083 mol) of 1-chloro-5-hydroxy-5-methylhexane (Example 1a) and 11.5 g (0.083 mol) of potassium carbonate in 500 ml of dimethylformamide was stirred at 110 ° C for 18 hours. The reaction mixture was filtered while hot and the filtrate was evaporated under reduced pressure. The oily crude product which slowly crystallizes is preferably purified by filtration through a silica gel column using a 10: 1 mixture of chloroform and methanol, followed by recrystallization from ethyl acetate with the addition of petroleum ether at boiling point.

Yield: 15.2 g (57.2% of theory).

Melting point: 105 to 107 ° 0.

Analysis for:

ΐΐ ^ ^ 26 ^ ^ ^θ (Molecular Weight 354.4) calculated C 54.22, H 7.39, N 15.81% Found: C 53.87, H 7.47, 15.71% H.

Tabulkal

Compounds of formula I:

Compound «- Temperature No. ^RR · ^R Melting point (° C)

-CHCH,

228-230

- (oh ₂ ) ₄ -c-ch ₃

OH

CH ₃

H ₃ C-O- (CH ₂ ) ₄ -CH ₃

AND

OH • Ch.1 ^J. (CH _{2) 4} -C-OH ₃

OH

93-95

CH.

- Ο ₃ Ηγ -CH ₃ - (CH ₂ ) ₄ -C-CH ₃

59-60

OK ·

en 272766 B2 Compound number

R ‘

R 'melting point (° C)

OHCH-CH _{(CH2) 4-CH 3} -c

AND

OH

106-107

GH.

H ₃ CC- (CH ₂ ) ₄ OH

-CH ₂ -CH ₂ -oc ₂ h ₅

102-103

CH ₆ H ₃ CC- (CH ₂ ) ₄ - -CH ₃

-H

192-193

OH

CH.

H ₃ CC- (CH ₂ ) ₄ - -CH ₃

O

CH ₂ -C-CH ₃

78-80

OH compound number melting point (° C)

CH.

OH δ h ₃ c- (CH ₂ ) ₄ -CH ₃ • CH ₂ -CH-CH ₃

119-120

OH

CH-CH.

h ₃ cc- (ch ₂ ) ₄ -Ο ₃ Ηγ

- 82

OH

OHIO h ₃ c-ch ₂ - c- (ch ₂ ) ₄ -CH 83 - 84

CH.

0Η

-CHCHh ₃ CO- (CH _{2) 4} -CH.

.ch ₂ -c-ch ₃

121 - 123

0Η

OH

CS 272766 £ 2 Compound pL Number ^K Melting point (° 0)

CH.

I ^J

HC-C- _(CH) -CH. JIJ 3

OH

-C ₃ H ₇ 96-98 ch ₃

AND

H ₃ CC- (CH ₂ ) ₅ -C ₂ H ₅

-CH ₃ ,. 86-87

OH

CH.

1 h ₃ CC- (CH ₂ ) ₄ - -CH ₃

AND

OH

-CH

120-121

H ₃ CC- (CH ₂ ) ₅ - -CH ₃

112-113

OH

OS 272766 B2 Compound 1 _p 2

R ^Λ number melting point (° C)

CH I 3

H ₃ CC- (CH ₂ ) ₅ OH

-CH 3 ^H 7

- 94

CH.

H ₃ CC- (CH ₂ ) ₄ -C ₂ H ₅

OH

-CH.

ch;

H ₃ CC- (CH ₂ ) ₄ -C ₂ H ₅ -C ₆

- 71

OH

-CH,

I ³

Η ₃ σ-ΟΗ ₂ -Ο- (0¾) ₄ - -0¾

OH

86-87 Compound No. ^R

melting point (° C)

CH.

AND

H ₃ CC- (CH ₂ ) ₃ - -CH ₃

OH

CH ₃

AND

H ₃ CC- (CH ₂ ) ₃ -C ₂ H ₅

OH

CH.

I ^J

H ₃ CC- (CH ₂ ) ₃ -C ₂ H ₅

OH

CH.

I ³

H ₃ CC- (CH ₂ ) ₂ - -CH ₃

OH

-CH

-c ₃ h ₇

117-118

95

- 93

146-147 compound number

R ^J melting point (° C)

CH.

AND

H ₃ CC- (CH ₂ ) ₂ -C ₂ H ₅

OH

-ch ₃ '

122

CH.

AND

H ₃ CC- (CH ₂ ) ₂ - -CH ₃

OH

135-137 ^ 4¾

CH-cis - (CH ₂ ) ₂ - c -CH ₃

- 70

OH

CH 27 H ₃ CC- (CH ₂ ) ₅ • ch ₃ -ch ₂ -o-ch ₃

- 54

OH compound _ temperature number ^R RR _{melting point (} o _c)

CH 28 'H ₃ CC- (CH ₂ ) ₄ - -CH ₃ • CH ₂ O-CH ₃

- 94

OH

CH-,

H ₃ CC- (CH ₂ ) ₄ -C ₂ H ₅

OH

CH,

AND

H ₃ CC- (CH ₂ ) ₃ - -CH ₃ • CH ₂ -O-CH ₃ ch ₂ -o-ch ₃

OH

CH ₃ H ₃ CC- (CH ₂ ) ₃ -C ₂ H ₅ • ch ₂ -o-ch ₃

OH

63

- 101

- 96

GS 272766 Έ2 compound

Number

Melting point (° G)

32 CH. 1 H ₃ CC- (CH ₂ ) ₂ - OH -CK ₃ -CH ₂ -O-CH ₃ 105-107 33 ch ₃ 1 H ₃ CC ~ (CH ₂ ) ₄ - -CA -CH ₂ -OC ₂ H ₅ 68 - 70 34 OH CH, ¹³ H _{3 c -} (OH ₂ ) ₄ - OH. H ₃ CO- (CH ₂ ) ₂ - -CH ₃ -CHg-O-C-JH? 83-85 35 -ch ₃ CH ₃ - (CH ₂ ) ₄ -C-CH ₃ 63-65

OH compound number

R * melting point (° C)

36 h ₃ cc- (CH ₂ ) ₄ -OH -CH ₃ - (CH ₂ ) ₂ -O-CH ₃ 98-99 37 ch ₃ 1 h ₃ cc- (ch ₂ ) ₄ - 1 -c ₂ H ₅ - (CH ₂ ) ₂ -O-CH ₃ 71 OH CH ₃ 38 H ₅ C ₂ -O- (ch ₂ ) ₂ - -CH ₃ - (CH ₂ ) ₄ -C-CH ₃ 77 - 79 gh ₃ 1 h ₃ cc- (ch ₂ ) ₄ - I -ch ₃ 1 OH - (ch ₂ ) _{2 -} gc ₂ h ₅ 75 1 OH 40 ch ₃ 1 h ₃ cc-cch ₂ ) ₄ - -g ₂ h ₅ - (CH ₂ ) ₂ -OC ₂ H ₅ 52-54

OH compound number

R 'melting point (° 0)

41 h ₃ co- (ch ₂ ) ₃ - -CH ₃ 1 ³ - (CH _{2) 4} -C-CH ₃ I 45 - 47 Γ ³ - 1 OH 42 H ₃ CC- (CH ₂ ) ₄ - 1 -CH ₃ - (ch ₂ ) ₃ -o-oh ₃ 83-84 43 OH CH. 1 h ₃ cc - (ch ₂ ) ₄ - -c ₂ h ₅ - (CH ₂ ) ₃ -O-CH ₃ 72-73 44 Íh CH. 1 h ₃ cc- <ch ₂ ) ₄ - -ch ₃ -CH ₂ -O- (CH ₂ ) ₂ - O-CH ₃ 88-89

OH compound pl number melting point (° C)

H ₃ CC- (CH ₂ ) ₄ -C ₂ H ₅ -CH ₂ -O (CH ₂ ) ₂ -O-CH ₃ oil

OH

AND

CH.

I _and 46 H ₃ CC- (CH ₂ ) ₂ - -C? -CH ₂ -O- (CH ₂ ) ₂ -O-CH ₃ 97-98OH

CH.

H ₃ CC- (CH ₂ ) ₄ - -CH ₃ - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -0C H ₅ oil

OH

CH48 H ₃ CC- (CH ₂ ) ₄ - -C ₂ H ₅ - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -0C ₂ H ₅ oil

OH

OS 272766 Bg compound number} melting point (° C)

CHCH.

H.C-C-CH 2 I

OH

-ch _3- (ch ₂ ) ₄ -c-ch ₃

Ih

- 67 hp ₃

AND

H ₃ CC- (CH ₂ ) ₄ - -CH ₃ -CH ₂ -CH ₂ -CH ₂ -Off 78-80

OH

CH.

H ₃ CC- (CH ₂ ) ₄ - -CH ₃ - (CH ₂ ) ₄ -C-CH ₃ oil

OH

CHOH

H ₃ CC- (CH ₂ ) ₄ -CH ₃ - (CH ₂ ) ₄ -CH-CH ₃ 69-71

OH

CS 272766 332 Compound number ^Γ

R ² melting point (° C)

H ₃ CC- (CH ₂ ) ₄ - -CH ₃

OH h-c-ch- (ch ₂ ) ₄ -ch ₃ ch ₃

- (ch ₂ ) ₄ -c-ch ₃

OH

CH ₃

- (ch ₂ ) ₄ -c-ch ₃

OH oil oil

CH.

H ₃ CC- (CH ₂ ) ₄ -CH ₃ - (CH ₂ ) ₂ -CH-CH ₂ ^OH OH OH

116-118

CH.

H ₃ CO- (CH _{2) 4} • CH ₃ -CH ₂ -CH = CH ₂

105-107

OH

OH OH

Testing of pharmacological properties and results of pharmacological tests

1. Effect on peripheral arterial blood flow disorders

In the last decade, the notion of the pathophysiology and hence the medical treatment of chronic peripheral arterial occlusions has seen a remarkable turn in that the scientific and therapeutic interest has shifted increasingly from macrocirculation to micro-circulation, and in particular to the capillary bed through which the adjacent tissue is nourished. by a substrate exchange that is mediated by diffusion. As a result, microcirculation disorders result in deficiencies in cellular supply and the resulting tissue ischemia, so treatment should be directed to suppress the pathological inhomogeneity of capillary nutritional blood flow and thereby: - normalize the local partial oxygen pressure (pOg) in ischemic tissue.

Therefore, testing the compounds of the present invention for their improved tissue delivery effect was performed by measuring partial pressure of oxygen in isehemic skeletal muscle in an experiment described by DW LUBBERS (Prog. Resp. Res. 3, (Karger, Basel) 1969), pp. 136-146) and M, KESSIER (Prog. Resp.

Res. 3 (Karger, Basel 1969), pp. 147-152 and Anesthesiology 45 (1976), p. 184), using Pentoxifylline as a comparative standard formulation in experiments.

Male Beagle dogs in natriumpentoharbital anesthesia (35 mgAs ί · ρ ·) were used as test animals in which Arteria femoralis and a certain area of the lower leg were released on the right hind limb and Vena femoralis was released on the left hind limb for infusion of the preparation and Arteria femoralis for measuring blood flow and appropriate cannulas are inserted. The animals were given Alcuronium chloride (0.1 mg / kg iv and then 0.05 mg / kg ip every 30 minutes thereafter for relaxation) and artificial respiration was introduced to prevent spontaneous muscle contraction with a negative effect on the measurement of partial oxygen pressures and On the other hand, an even oxygen supply for breathing was ensured.

Another catheter connected to the Vena femoralis of the right hind limb was used to control lactate concentration in venous blood. The multi-conductor surface electrode wire is now connected to the exposed muscle area to continuously register the partial pressure of oxygen. Once the oxygen partial pressure curve has stabilized, the Arteria femoralis is closed with a clamp, whereupon the oxygen partial pressure in the muscle supplied by this vessel drops rapidly and then slightly increases again due to spontaneous opening of the collateral vessels and finally settles at a value substantially lower. compared to healthy muscle.

At this point in time, the test substance is administered in an aqueous solution of a cell intravenous infusion (i.v.) (0.6 mg / kg / min) or at a dose of 25 mg / kg intraduodenally (i.d.) and the increase in partial pressure of oxygen in isehemic muscle is measured. Each time before and after the closure as well as after administration of the substance, venous blood is collected to determine the washed lactate and to check the physiological state of the animals. In addition, the gas concentration (oxygen partial pressure and carbon dioxide partial pressure) and the pH value in the arterial blood of the ischemic limb are examined at the beginning and at the end of each experiment.

The maximum increase in oxygen partial pressure in% after administration of the substance during vascular occlusion (n = 2-11) is used as a measurement parameter for the efficacy of the formulation in a single experiment.

From these measured values, a dimensionless activity index W is calculated for each compound by expressing the value of the percentage of positive experiments and the mean increase in oxygen partial pressure in% given by each positive value, taking into account both interindividual differences in muscle vascular topology and individual differences in response application of the compound, thereby allowing a more reliable comparison of the efficacy of the individual compounds.

GS 272766 B2.42

2. Effect on regional blood circulation in the brain

The effect of the compounds produced by the process of the invention on the regional blood circulation of the brain 30 is investigated by PA GIBBS heat conduction technique (Proc. Soc. Exp. Biol. (). Y.) 31 (1933), p. 141 et al.), H. HENSELa. 43 (1956), p. 477 et al.) And E. BETZe (Acta Neurol. Scand. Suppl. 14 (1965), p. 29-37) on both sexes in natriumpentobarbital narcosis (35 mg / kg ip), with again, the standard Pentoxifylline therapeutics are used for comparison purposes. In this method, a heat conduction probe located on the surface of the brain in the area of Gyrus marginalis frontalis is used to determine heat conduction from the heating point to the adjacent temperature measuring point in the probe, which corresponds directly to the blood flow to the brain. Thus, the percent increase in heat conduction value X after administration of the formulation represents a measure of improved blood flow.

The compounds are administered intravenously in aqueous solution. The dose is 3 mg of test substance per kg body weight. For each test preparation, 3 to 5 individual experiments are performed and the mean percent increase in brain blood flow is determined from the measured values obtained.

3. Acute toxicity:

LD ^ q values are determined by standard methods using mortality observed over 7 days in mice (NMRI) following a single intravenous (i.v.) or intraperitoneal (i.p.) administration.

The results of these tests, which clearly demonstrate the superiority of the compounds of formula I produced by the process of the invention over the standard formulation of Pentoxifylline, are summarized in Tables 2 and 3 below:

Table 2

Effect on peripheral arterial blood flow disorders in the dog closure model and acute toxicity in mice

compound number closure model toxicity route of administration: i, v: 0.6 mg / kg / min i.d .: 25 mg / kg efficiency index W (cf. page 89) LD in mg / kg (mouse) 3 i.v. 1650 i.v .: 100-200 i.d. 1250 4 i.v. 1300 i.v .: 100-200 ^J 5 i.v. (0.3 mg / kg / min) 2080 i.v .: 150-300 i.d. 2909 i.p .: 300-600 6 i.d. 700 i.v .: > 200 8 i.v. 1400 i.v .: > 200 10 1 · d · 1965 i.v ,: > 200 12 i.v. 866 i.d. 2337 i.v .: > 200

Table 2 (continued)

compound number model of closure application: i.v .: 0.6 mg / kg / min i.d .: 25 mg / kg efficiency index W (cf. page 89) LDg ₀ toxicity (mouse) v n g / kg 14 i.v. 960 i .v .: > 200 16 i. v. 999 i.p .: 150-300 ¹⁷ i.v. 1525 i.v .: > 200 18 i.v. 1578 i.v .: 100-200 28 i.d. 2100 i.v .: > 200 32 i.v. i.d .. 2650 566 i.v .: > 200 37 i.v. i.d. 1400 950 i.v .: > 200 39 i. v. i.d. 1567 1996 i.v .: > 200 44 i. v. 1199 i.v .: > 200 50 i.v. i.d. 2631 733 i.v .: > 200 Pentoxy- i.v. 891 i.v .: 187-209 fyllin i.d. 643 i.p .: 219-259

Table 3

Effect on regional blood supply to the brain of narcotized, intravenous cats

administration of 3 mg / kg and acute toxicity in mice LDtjQ toxicity in mg / kg compound number median increment of cerebral blood flow as in% 3 15.5. - i # v. 100 - 200 9 9.4 i.v. 100 - 200 16 25.8 i.p. 150-300 17 9.4 i.v. > 200 18 9.4 i.v. 100 - 200 22nd 12.0 i.v. > 200 27 Mar: 10.3 i.v. > 200 43 19.8 i.v. > 200 48 14.6 i.v. > 200 pentoxi- 8.6 i.v. 187 - 209 fyllin i.p. 219-259

The unambiguous predominance of the compounds produced by the process of the invention, in particular against Pentoxifylline, the xanthine derivative most commonly used for the treatment of peripheral and cerebral blood flow disorders, can be conclusively confirmed by other special experiments.

It is now well known that pharmaceuticals that exclusively act to augment blood vessels or agents with a very potent vasodilator component of action are unsuitable for the treatment of microcirculation disorders, since, on the one hand, the physiological vasodilator reserve is usually completely depleted, while on the other thus, the danger of Steale's phenomenon, which means a harmful redistribution of the nutritional blood flow in microcirculation, leading to the burden of already under-supplied diseased tissue. For this reason, the inhibitory effect on vascular contraction induced on the isolated washed ear of the rabbit by norfenephrine was investigated. For example, compound 5 shows no inhibitory effect on norfenephrine up to a concentration of 100 µg / ml, while Pentoxifylline extends over a concentration range of 10 to 100 µg / ml depending on the dose of the vessel which has been narrowed by norfenephrine.

In a chronic experiment in rats with one-sided closure of Arteria-iliaca, it can be shown that the compounds of formula I can favorably influence metabolism in ischemic skeletal muscle. For example, if animals are treated for 5 weeks with compound number 5, with daily intraperitoneal administration of 3 mg / kg / ip each day, the histochemical staining method showed that both muscles of the limb (Tibialis anterior and Extensor digitorum) were examined longus) the proportion of oxidized fibers increased substantially. In contrast, Pentoxyfillin did not show any direct effect on muscle metabolism in a comparable experiment conducted in the same manner.

The predominance of the xanthines of formula I has also been shown in another chronic test in which the effect of contractility of the ischemic skeletal muscle of rats with ligated right Arteria femoralis is examined. Animals are dosed for 20 days with the respective test preparation at a daily oral dose of 25 mg / kg via an esophagus probe. The degree of ischemic muscle fatigue in electrical irritation is then determined with about 80 contractions / min contraction intensity decrease after 1, 15 and 40 minutes of stimulation compared to untreated control animals. Obviously, for example, compound number 5, by optimizing metabolism, significantly improves muscle performance in the ischemic limb, e.g. which even achieved normal contractility values as in the left healthy (non-ischemic) muscle of untreated animals. This improvement coincides with increased control of mitochondrial respiration (RCR = Respirators Control Rate). Pentoxifylline proved to be ineffective in these experiments.

The compounds produced by the process of the invention are therefore also suitable for the treatment of muscular energy metabolism disorders of various origins, in particular mitochondrial myopathies.

3 *

SUBJECT OF IRONIAILS

Claims (5)

A process for the preparation of a tertiary, hydroxyalkylxanthine of the formula I in which at least one of the radicals R 1 and iP is a tertiary hydroxyalkyl group of the formula Ia E ⁴ AND - (CH ₂ ) _n -C-CH ₃ (Ia) OH where R ⁴ represents alkyl having up to 3 carbon atoms and n is an integer of 2 to 5, and if only one of the radicals R or R represents such a tertiary hydroxyalkyl group of the formula Ia, then the other of these radicals represents a hydrogen atom or an aliphatic hydrocarbon an E group having up to 6 carbon atoms, the carbon chain of which is optionally interrupted by up to 2 oxygen atoms or is optionally substituted by one oxo group or up to two hydroxyl groups, said oxo group and hydroxyl groups being separated from the ring nitrogen atom by at least 2 carbon atoms; R represents an alkyl group having 1 to 4 carbon atoms, characterized in that the 3-alkylxanthines of formula II (II) are alkylated in which: R is as defined above, A represents a hydrogen atom, a group R 1 or a group of the formula Ia and B is hydrogen, R1, benzyl or diphenylmethyl, at least one of A and B being hydrogen, in aprotic organic solvents, alcohols, aromatic or halogenated hydrocarbons, pyridine, optionally also in admixture with water at the reaction temperature between 0 ° C and the boiling point of the reaction mixture, in the presence of basic condensing agents, such as inorganic or organic bases, or in the form of their salts, at position 1 and / or position 7 in a single step or sequentially by treatment with at least 1 to 2 moles of alkylating agent common X - Q (III), of formula III wherein X Q represents a halogen atom or a sulfonic acid ester or phosphoric acid ester residue and represents a tertiary hydroxyalkyl group of the formula Ia, a benzyl group or a diphenylmethyl group, followed by a reductive cleavage of the residue B if the residue is a benzyl group or a diphenylmethyl group; by catalytic hydrogenolysis at atmospheric pressure or at a pressure of up to 1.0 MPa at a temperature of 20 to 100 ° C, or by hydrolytic elimination of an alkoxymethyl or alkoxyalkoxymethyl residue from the position of residue B under acidic conditions at temperatures below 100 ° C and optionally subsequent reduction of the keto group to an alcohol function when A or B is an oxoalkyl group by treatment with a metal hydride at a temperature between 0 ° C and the boiling point of the reaction medium. 2. Process according to claim 1, characterized in that the corresponding compounds of the formulas II and III are used as starting materials to give the compounds of the formula I: 2 1 wherein R is methyl or ethyl and R and R ^J are as defined T 3 in the roll 1 with only one of the two substituents R or R ^j represents a tertiary hydroxyalkyl group of the formula la as defined in point 1. 3. Process according to claim 1 or 2, characterized in that the corresponding compounds of the formulas II and III are used as starting materials to give compounds of the formula I, 12 3 13 wherein R, R and R have the meaning given in 1 or 2, wherein R or R represents a ((R) -1-hydroxy- (R) -1-methyl) pentyl, - hexyl or -heptyl group. Process according to one or more of Claims 1 to 3, characterized in that the corresponding compounds of the formulas II and III are used as starting materials to give compounds of the formula I in which R ³ represents a tertiary hydroxyalkyl group of the formula Ia, preferably R ³ represents a ((R) -1) -hydroxy-1) -methyl) pentyl, -hexyl or -heptyl group, R represents a methyl, ou or ethyl group, and R represents a. in particular an alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms or an alkoxyalkyl group having 1 to 4 carbon atoms in both the alkoxy and alkyl moieties. 5. Process according to claim 4, characterized in that the corresponding compounds of the formulas II and III are used as starting materials to give the compounds of the formula I in which: Wherein R is 5-hydroxy-5-methylhexyl, R is methyl and R1 represents an ethoxymethyl group.